Moderate hyperthermic heating encountered during thermal ablation increases tumor cell activity

Abstract

Purpose: The aim of this study was to determine whether moderate hyperthermic doses, routinely encountered in the periablational zone during thermal ablation, activate tumor cells sufficiently to secrete pro-tumorigenic factors that can induce increased proliferation. Material and methods: R3230 rat mammary tumor cells and human cancer cell lines, MCF7 breast adenocarcinoma, HepG2 and Huh7 HCC, and HT-29 and SW480 colon adenocarcinoma, were heated in to 45 ± 1 C or 43 ± 1 C in vitro for 5-10 min and incubated thereafter at 37 C for 1.5, 3 or 8 hr (n ¼ 3 trials each; total N ¼ 135). mRNA expression profiles of cytokines implicated in RF-induced tumorigenesis including IL-6, TNFa, STAT3, HGF, and VEGF, were evaluated by relative quantitative real-time PCR. HSP70 was used as control. c-Met and STAT3 levels were assessed by Western blot. Finally, naïve cancer cells were incubated with medium from R3230 and human cancer cells that were subjected to 43-45 C for 5 or 10 min and incubated for 3 or 8 h at 37 C in an xCELLigence or incuCyte detection system. Results: Cell-line-specific dose and time-dependent elevations of at least a doubling in HSP70, IL-6, TNFa, STAT3, and HGF gene expression were observed in R3230 and human cancer cells subjected to moderate hyperthermia. R3230 and several human cell lines showed increased phosphorylation of STAT3 3 h post-heating and increased c-Met following heating. Medium of cancer cells subject to moderate hyperthermia induced statistically significant accelerated cell growth of all cell lines compared to non-heated media (p < 0.01, all comparisons). Conclusion: Heat-damaged human tumor cells by themselves can induce proliferation of tumor by releasing pro-tumorigenic factors.

Sub-Lethal Hyperthermia Enhances Anticancer Activity of Doxorubicin in Chronically Hypoxic HepG2 Cells Through ROS-Dependent Mechanism

“…It is well known that during thermal ablation, the temperature inside the ablation zone decreases from center to margin where the temperature is sub-lethal and residual viable tumor cells often exist, potentially causing tumor relapse [16,17]. In our previous study, we reported that chronic hypoxia, an important characteristic following TACE, can trigger chemoresistance to doxorubicin in HepG2 cells [18].…”

How large is the periablational zone after radiofrequency and microwave ablation? Computer-based comparative study of two currently used clinical devices

“…As yet, no thresholds have been established for assessing the extent of the periablational zone based on Ω. However, although there is still no accurate assessment of the scope of this entire area, there do exist experimental data that provide some insight on the subject and may be used as a guide in selecting suitable thresholds; for example, the study by Markezana et al [ 1 ] reports a statistically significant accelerated growth of tumor cells subjected to moderate hyperthermia, especially when heated to 43 and 45 °C for 5 and 10 min. We used these four combinations of temperature–time values to estimate the range of Ω to define the periablational zone by means of the Arrhenius damage model with the following parameters: frequency factor A = 7.39×10 39 s −1 and activation energy Δ E = 2.577×10 5 J/mol [ 13 ].…”

“…As 55% of cells are still viable at a damage index of Ω=0.6 and 12% at Ω=2.1, this means that the periablational zone includes both viable cells and those damaged by heating, which can range from around 55% at Ω=0.6 to 88% at Ω=2.1. It must be recognized that the entire periablational zone is composed of cells subjected to moderate hyperthermic heating and is not necessarily limited to the thermal doses considered by Markezana et al [ 1 ], and that if different Ω values were to be found in future studies this would mean redefining the periablational zone and changing some of the conclusions.…”

“…(b) Relation between percentage of living cells after heating and index X obtained from the Arrhenius damage model, which associates temperature with exposure time using a first-order kinetics relationship. Periablational zone was assumed to be between X ¼ 0.6 and X ¼ 2.1 (values derived from experimental data in [1], see text for details), while coagulation zone was defined by the X ¼ 4.6 contour, which represents 99% probability of cell death.…”

“…Energy-based high-temperature ablative therapies such as radiofrequency ablation (RFA) or microwave ablation (MWA) have demonstrated their ability to thermally destroy tumors by creating a coagulation zone that covers a 0.5–1 cm safety margin around the entire tumor. However, evidence is now emerging that any tumor regions that do not reach ablative temperatures may be subsequent promoters of tumor growth [ 1 ]. This area, called the periablational zone , is always present around the coagulation zone ( Figure 1(a) ).…”